Abstract
Objectives: This study aimed to detect the time window of vascular normalization during anti-vascular treatment using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Simultaneously, we evaluated the tumor invasiveness and vasculogenic mimicry and performed synthetic assessment of treatment efficacy of angiogenesis inhibitor combined with conventional chemotherapy using IVIM-DWI.Materials and Methods: HCT116 cells were subcutaneously administered into the right flank of BALB/C nude mice to build a colon cancer xenograft model. Thirty-two tumor-bearing mice were randomly divided into four groups and intraperitoneally administered with normal saline (Group A or control group), bevacizumab (Group B), oxaliplatin monotherapy (Group C), and oxaliplatin combined with bevacizumab (Group D). The IVIM-DWI was performed on days 0, 3, 6, 9, 12, and 15 after the treatments. Another 51 tumor-bearing mice were included in the pathological examinations. α-Smooth muscle actin (SMA) and CD31 double-staining, periodic acid-Schiff (PAS) and CD31 double-staining, hematoxylin and eosin (HE), Ki-67, and E-cadherin staining were performed. The tumor growth and dynamic change of each parameter were noted.Results: The mice in Group D manifested the smallest tumor volume and highest tumor inhibition rate. Microvessel density was significantly decreased but accompanied by increased vasculogenic mimicry after antiangiogenic treatment. The trend was reversed by oxaliplatin treatment. Treated with bevacizumab, the vessel maturity index shared a similar trend with D* and f-values during days 3–12, which slowly increased from days 0 to 9 and then decreased briefly. D-value significantly correlated with vasculogenic mimicry and Ki-67, while D* and f-values showed positive correlations with microvessel density and E-cadherin, an indicator of epithelial–mesenchymal transition.Conclusion: Oxaliplatin performed an inhibited effect on vasculogenic mimicry. Bevacizumab can enhance the tumor chemotherapy through vascular normalization within a transient time period, which can be detected by IVIM-DWI. D* and f-values are able to predict the tumor invasiveness while D is superior in reflecting vasculogenic mimicry and Ki-67 expression during antitumor treatment.
Highlights
Tumor vascularization plays an important role in tumor growth, invasion, and metastasis
The mice for the magnetic resonance imaging (MRI) examinations were randomly divided into four groups and intraperitoneally injected with normal saline (Group A or control group), bevacizumab (5 mg/kg; Group B), oxaliplatin (4 mg/kg; Group C), and oxaliplatin combined with bevacizumab (Group D) on days 1, 4, 7, 10, and 13
An obvious inhibitory effect on tumor growth was shown as early as 6 days after the treatment with a much slower growth rate in tumor volume during treatment
Summary
Tumor vascularization plays an important role in tumor growth, invasion, and metastasis. The lack of adequate oxygen supply for tumor growth will induce the formation of a hypoxia microenvironment. In order to counteract the severe condition, the tumor cells and tumor microenvironment will upregulate the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α) and subsequently perform a series of adaptive changes. Epithelial–mesenchymal transition (EMT) will be induced by activating HIF-1α [1], and the tumor cells will lose their epithelial phenotypes but acquire mesenchymal phenotypes with migration ability, enhancing the tumor invasiveness and the metastatic potential. E-cadherin, which is mainly expressed on the epithelial cell membranes, is proved to be most correlated with tumor invasiveness and metastasis and considered as an important indicator of EMT [2, 3]
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